PROJECT 1: IMMUNE MECHANISMS LINKING OBESITY TO THE DEVELOPMENT OF HYPERTENSION DURING PREGNANCY. RESEARCH SUMMARY Preeclampsia (PE), characterized by new-onset hypertension during pregnancy, is estimated to affect 1 in 20 of all pregnancies in the U.S. It is a leading cause of maternal death and a major contributor to maternal and perinatal morbidity. Unfortunately, the only effective treatment is premature delivery to remove the ischemic placenta. Strikingly, the incidence of PE has increased by 40% over the last several decades as a result of a significant increase in risk factors such as obesity. The % of reproductive-age women who are overweight or obese has increased almost 60% in the last 30 years. Despite the fact that obesity is the leading attributable risk factor for PE, the pathophysiological mechanisms whereby obesity and obesity-related metabolic factors such as leptin increase the risk for the development of this maternal disorder are unclear. However, growing evidence suggests that pro-inflammatory cells and cytokines are important mechanisms responsible for the marked increase in risk of developing PE in obese pregnant women. In obese PE women, there are increased circulating and placental populations of CD4+ T helper cells, but whether the cells drive the development of hypertension during obese pregnancies are unclear. The central hypothesis to be tested is that obesity and chronic excess of the specific obese-related metabolic factor leptin (hyperleptinemia) drive increases in CD4+ T helper cells that elicit the development of hypertension via TNF? signaling. The ultimate goal is to uncover mechanistic targets using novel animal models to develop cutting-edge treatment strategies to prevent the pathogenesis of PE, such as in the growing obese population in the following specific aims: AIM 1: To test the hypothesis that hypertension during obesity or chronic leptin excess is mediated by TNF? during pregnancy. AIM 2: To test the hypothesis that obesity or chronic leptin excess increases T cell activation-mediated hypertension and CD4+ T helper cell counts and their secretion of TNF?. AIM 3: To test the hypothesis that CD4+ T helper cells from obese or chronic leptin excess hypertensive pregnant rats are pro-hypertensive via TNF? signaling.